Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, missed school, & are associated with an increased mortality rate. There are no current therapies to relieve vaso-occlusion, with interventions limited to hydration and analgesia. Nitric oxide (NO), produced by the 5-electron oxidation of L-arginine, is a potent vasodilator & exerts pleiotropic effects on vascular & circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, & modulation of ischemia-reperfusion injury, all pathways adversely affected during VOE. We have found that pediatric SCD patients admitted with VOE have depleted plasma L-arginine levels. Additionally, we have now completed a single-center randomize, double-blinded, placebo-controlled trial of arginine therapy in 54 children with VOE requiring hospitalization. We observed a reduction in total opioid use (mg/kg) by 54% and significantly lower pain scores at discharge in children who received 5 days of 100 mg/kg/dose TID IV L- arginine therapy compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of approximately 17 hours. We now propose to extend these results to a phase II trial of L-arginine for VOE to gather more efficacy and safety data. We hypothesize that arginine is a safe & inexpensive intervention with narcotic-sparing effects in pediatric SCD patients with VOE. Aim 1 of this study will determine the efficacy of IV arginine therapy on the primary endpoint, total parenteral opioid use (mg/kg) in children with SCD & VOE & to evaluate whether a loading dose provides additional benefits over standard dose (Efficacy). Aim 2 will monitor for potential toxicities associated with a loading dose & repeat administration of IV L-arginine (Safety). Aim 3 will characterize alterations in the arginine metabolome in children with SCD and VOE, and evaluate how it is impacted by IV arginine therapy (Exploratory). This proposal will provide essential data for product development including the planning of a future multi-center Phase 3 trial, which will ultimately help gain product approval for SCD. Acute care of patients with SCD & pain in the ED is a neglected area of research. The results of this study may ultimately lead to change in clinical practice for children with SCD in both the ED & inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of vaso-occlusion and pain are needed in SCD.